Decline of miR‐124 in myeloid cells promotes regulatory T‐cell development in hepatitis C virus infection

Summary Myeloid‐derived suppressor cells (MDSCs) and microRNAs (miRNAs) contribute to attenuating immune responses during chronic viral infection; however, the precise mechanisms underlying their suppressive activities remain incompletely understood. We have recently shown marked expansion of MDSCs that promote regulatory T (Treg) cell development in patients with chronic hepatitis C virus (HCV) infection. Here we further investigated whether the HCV‐induced expansion of MDSCs and Treg cells is regulated by an miRNA‐mediated mechanism. The RNA array analysis revealed that six miRNAs were up‐regulated and six miRNAs were down‐regulated significantly in myeloid cells during HCV infection. Real‐time RT‐PCR confirmed the down‐regulation of miR‐124 in MDSCs from HCV patients. Bioinformatic analysis suggested that miR‐124 may be involved in the regulation of signal transducer and activator of transcription 3 (STAT‐3), which was overexpressed in MDSCs from HCV patients. Notably, silencing of STAT‐3 significantly increased the miR‐124 expression, whereas reconstituting miR‐124 decreased the levels of STAT‐3, as well as interleukin‐10 and transforming growth factor‐β, which were overexpressed in MDCSs, and reduced the frequencies of Foxp3+ Treg cells that were developed during chronic HCV infection. These results suggest that reciprocal regulation of miR‐124 and STAT‐3 in MDSCs promotes Treg cell development, thus uncovering a novel mechanism for the expansion of MDSC and Treg cells during HCV infection. HCV infection deregulates miR‐124 expression in MDSCs, which in turn, alters STAT‐3 and regulatory cytokine (IL‐10 and TGF‐β) expression. STAT‐3 can reciprocally regulate miR‐124 expression in MDSCs. The reciprocal regulation of miR‐124 and STAT‐3 in MDSCs promotes Foxp3+ Treg cell development; hence reconstitution of miR‐124 and/or inhibition of STAT‐3 may provide a novel approach for HCV immunotherapy.